Angiogenesis is a tightly regulated process and its dysregulation can lead to development and progression of diseases such as tumor growth, diabetic retinopathy, tissue and organ malformation, and cardiovascular disorders [Folkman and D'Amore, Cell 87, 1153 (1996); Hanahan and Folkman, Cell 86, 353 (1996); Folkman and Shing, J. Biol. Chem. 267, 10931 (1992); Folkman, Nat. Med. 1, 27 (1995)]. Positive angiogenic regulators include basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), which are both potent mitogens and strong chemoattractants for endothelial cells [Dusak et al., J. Natl. Cancer Inst. 85, 121 (1993); Kim et al., Nature 362, 841 (1993)]. One example of a negative regulator is angiostatin which inhibits endothelial cell proliferation in vitro and suppresses tumor growth in animals [O'Reilly et al., Cell 79, 315 (1994): O'Reilly et al., Nat. Med. 2, 689 (1996)]. Angiostatin is a fragment of plasminogen (Pg) consisting of either the first three or four of its kringles. Pg kringle 5 (K5) also suppresses growth factor-stimulated angiogenesis via cell cycle-G1 arrest and induction of apoptosis; however, the cellular receptor(s) mediating these effects are unknown [Ji et al., Biochem. Biophys. Res. Commun 247, 414 (1998); Y. Cao et al., J. Biol. Chem. 272, 22924 (1997); Y. Cao et al., J. Clin Invest. 101, 1055 (1998); M. Dhanabal et al., Biochem. Biophys. Res. Commun. 258, 668 (1999)].
K5 confers on Pg the capacity to bind to human umbilical vein endothelial cells (HUVEC) with high affinity [Wu et al., Biochem. Biophys. Res. Commun. 188, 703 (1992)]. K5 also mediates binding of Pg to the streptococcal Pg activator streptokinase (SK) [Nihalani and Sahni, Biochim. Biophys. Res. Commun. 217, 1245 (1995); Lin et al., Biochemistry 39, 4740 (2000), GenBank Accession No. BZSO]. Sequence similarities between SK and the mitochondrial human voltage-dependent anion channel (VDAC1) exist, but a functional relationship between these proteins has not been shown [McCabe et al., Biochem. Mol. Med. 56, 176 (1995)].